David Plas, PhD, Associate Professor of Cancer Biology at the University of Cincinnati College of Medicine and holder of the Anna and Harold W. Huffman Endowed Chair in Glioblastoma Experimental Therapeutics, brings a fresh viewpoint from his background as a leukemia researcher to the problem of glioma, a stubbornly aggressive form of brain cancer. He notes that while many leukemias are treated more successfully than ever before, “therapies for glioma could stand some major improvements.”

Dr. Plas is among a cadre of researchers at the UC Cancer Institute whose expertise is being tapped by the Brain Tumor Center, which embraces both the Cancer Institute and the UC Gardner Neuroscience Institute. Together these talented researchers are homing in on the molecular profile of glioma, a cancer that develops from glial cells in the brain and whose most common form is glioblastoma multiforme. An estimated 13,000 Americans die of brain and other nervous system cancers each year.

“New therapy for brain cancer requires new drugs that target the major pathways used by cancer genes,” Dr. Plas says. “Unfortunately, targeted therapy has had limited success in brain cancer. We hope to adapt ideas from the world of leukemia research to improve targeted therapy for brain cancer.

With help from funds generated by the Huffman Endowed Chair in Glioblastoma, Dr. Plas and his laboratory team are investigating cancer cell signaling and cancer cell metabolism. Cancer cell signaling links cancer mutations to the cellular machines that drive cell growth and proliferation. By counteracting abnormal signaling through targeted therapy, the Plas team hopes to restore the “brakes” that restrain cancer cell metabolism and growth.

Targeted therapy.

Dr. Plas’s lab is focused on a protein known as S6 Kinase 1, or S6K1. S6K1 functions downstream of PTEN, a major tumor suppressor that is frequently mutated in glioma. The deficiency of PTEN occurs in all four molecular subtypes of glioblastoma.

Although S6K1 is frequently activated in human cancer, scientists have not fully explored the opportunities for targeting S6K1 as a cancer therapy. “We’ve only recently become able to target S6K1,” Dr. Plas says. “We are hoping to be on the front wave of targeting this pathway toward the development of S6K1 inhibitors.”

Immunotherapy

The Plas Lab is involved in the revolutionary new field of tumor immunology. “In new work for our group, we are beginning to explore how to incorporate anti-tumor immune responses into a regimen that includes the three traditional arms of cancer therapy: surgery, radiation and chemotherapy,” Dr. Plas says.

Metabolism

The Plas Lab is also working to understand how cancer cells are able to adapt to chemotherapy and survive. The lab’s experiments are focused on identifying and targeting mechanisms that permit these adaptive responses in cancer.
Dr. Plas is clearly excited about the developments. “We have an opportunity to use targeted therapeutics that have not been successfully applied in glioma therapy,” he says. “What draws our interest is the importance of the problem.”

BTC Research Portfolio

Work in the Plas Lab fits into a larger picture of innovative laboratories at UC that are developing molecule-targeted therapies for glioblastoma. The laboratories of El Mustapha Bahassi, PhD, and James Driscoll, MD, PhD, for example, are focusing on mutations on the epidermal growth factor receptor (EGFR). In glioblastoma, EGFR can lead to faulty signaling or “overactivation,” which causes cells to multiply too rapidly and to result in cancer. At least 30 to 50 percent of glioblastoma cases involve a malfunction of the EGF receptor. Dr. Plas notes that, “EGFR actually controls many different pathways. One of those pathways leads to S6Kinase1. So you can say that our work is related because these pathways are often interconnected.”

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